n-methylnaloxone and Opioid-Related-Disorders

Pruritus is a common adverse effect of opioid treatment. However, the mechanism by which pruritus is induced by opioid administration is unclear. In this study, we examined the effects of the intradermal injection of loperamide, a peripherally restricted opioid receptor agonist, on the itch sensation. When injected intradermally into the rostral part of the back in mice, loperamide elicited scratching behavior. We also examined the effects of the selective mu opioid receptor agonist [d-Ala², N-Me-Phe⁴, Gly⁵-ol]-enkephalin acetate (DAMGO), the selective delta opioid receptor agonist [d-Pen(2,5)]-enkephalin (DPDPE), and the selective kappa opioid receptor agonist U-50488H on scratching behavior in mice in order to determine which subtype is involved in opioid-induced pruritus. Following intradermal injection into the rostral part of the back in mice, DAMGO elicited scratching behavior, while DPDPE and U-50488H did not. This suggests that peripheral mu opioid activation elicits the itch sensation. Next, we focused on the treatment of opioid-induced itch sensation without central adverse effects. Naloxone methiodide is a peripherally restricted opioid receptor antagonist. In the present study, naloxone methiodide significantly suppressed scratching behavior induced by loperamide and DAMGO. These findings suggest that mu opioid receptors play a primary role in peripheral pruritus and that naloxone methiodide may represent a possible remedy for opioid-induced itching.

Topics: 3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cyclohexyl)-benzeneacetamide, (trans)-Isomer; Analgesics, Opioid; Animals; Antipruritics; Behavior, Animal; Dose-Response Relationship, Drug; Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; Enkephalin, D-Penicillamine (2,5)-; Injections, Intradermal; Loperamide; Male; Mice; Mice, Inbred ICR; Naloxone; Opioid-Related Disorders; Pruritus; Quaternary Ammonium Compounds; Receptors, Opioid, delta; Receptors, Opioid, kappa; Receptors, Opioid, mu; Skin

We previously reported the synthesis of three new opioid agonists as well as their in vitro and in vivo activity [Girón, R., Abalo, R., Goicoechea, C., Martín, M.I., Callado, L.F., Cano, C., Goya, P., Jagerovic, N. 2002. Synthesis and opioid activity of new fentanyl analogs. Life Sci. 71, 1023-1034]. One of them, N-[1-phenylpyrazol-3-yl]-N-[1-(2-phenethyl)-4-piperidyl)] propenamide (IQMF-4), showed an interesting antinociceptive activity. Intraperitoneally (i.p.) administered, it was as effective as fentanyl or morphine, being less potent than fentanyl but more so than morphine. The aim of the present work was to evaluate its antinociceptive effect by different routes of administration, using the hot plate test, and to investigate possible side effects, such as tolerance and withdrawal, in vitro, using the myenteric plexus-longitudinal muscle strip preparation from guinea pig ileum, and in vivo, using the hot plate test. IQMF-4 was more potent than morphine when administered per os (p.o.), but less potent when administered intracerebroventricularly (i.c.v.). By both routes, fentanyl is more potent that IQMF-4. When IQMF-4 was administered i.p., naloxone methiodide, a peripherally acting antagonist, was able to completely block its antinociceptive effect, whereas, after i.c.v. administration, the blockade was only partial. An interesting feature of the new compound is that it induces tolerance in vitro but not in vivo. Moreover, though in vitro withdrawal was not different from fentanyl or morphine, in vivo withdrawal symptoms were significantly less frequent in mice treated with IQMF-4 than in those treated with morphine or fentanyl. Although more assays are required, these results show that IQMF-4 appears to be a potent analgesic compound with an interesting peripheral component, and reduced ability to induce dependence.

Topics: Administration, Oral; Analgesics, Opioid; Animals; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Tolerance; Fentanyl; Guinea Pigs; Hot Temperature; Ileum; Injections, Intraperitoneal; Injections, Intraventricular; Male; Mice; Morphine; Muscle Contraction; Muscle, Smooth; Naloxone; Narcotic Antagonists; Opioid-Related Disorders; Pain; Pain Measurement; Pain Threshold; Piperidines; Propane; Quaternary Ammonium Compounds; Reaction Time; Substance Withdrawal Syndrome; Time Factors

Single injections of morphine induce a state of acute opioid dependence in humans and animals, measured as precipitated withdrawal when an antagonist is administered 4-24 h after morphine. Additional morphine exposure at daily or weekly intervals results in further increases in withdrawal severity, suggesting that acute opioid dependence reflects the early stages in the development of a chronic state of dependence. The current study evaluated the role of the nucleus accumbens (NAC), bed nucleus of stria terminalis (BNST), interstitial nucleus of posterior limb of the anterior commissure (IPAC), and central amygdala (CeA) in the expression of antagonist-precipitated suppression of operant responding for food as a measure of withdrawal from acute opioid dependence. Rats trained on a fixed-ratio 15 schedule received one or four daily injections of morphine, with the lipophobic opioid antagonist methylnaloxonium (16-2000 ng) infused into one of the brain regions or the lateral ventricle (i.c.v.) 4 h after the final morphine injection. After acute morphine methylnaloxonium was more potent upon infusion into the NAC (17.9-fold potency shift), BNST (6.8-fold) and CeA (5.5-fold) than it was upon i.c.v. administration. Following repeat morphine the NAC and BNST but not CeA continued to show greater sensitivity relative to i.c.v. infusion (12.9-, 8.7-, and 3.2-fold potency shifts, respectively). The IPAC was insensitive to methylnaloxonium after acute or repeat morphine at doses that reliably suppressed responding upon i.c.v. infusion (125-500 ng). Thus, among the components of extended amygdala examined in this study, rapid neuroadaptation within the nucleus accumbens and bed nucleus of the stria terminalis appear to play the most prominent role in antagonist-precipitated suppression of operant responding during the early stages in the development of opioid dependence.

Topics: Adaptation, Physiological; Amygdala; Animals; Conditioning, Operant; Male; Morphine; Naloxone; Narcotic Antagonists; Narcotics; Nucleus Accumbens; Opioid-Related Disorders; Quaternary Ammonium Compounds; Rats; Rats, Wistar; Septal Nuclei; Substance Withdrawal Syndrome

Opiate withdrawal behaviors in the infant differ from those of the adult. The neural circuitry underlying opioid withdrawal in the adult rat is well defined and includes the locus coeruleus (LC) and periaqueductal gray (PAG), with a minor role of the amygdala. Because the different behaviors that constitute the infant syndrome may be mediated by different neural circuits, we tested the hypothesis that these three sites are involved in opiate withdrawal. Pups were injected with morphine from day 1-6 after birth (b.i.d.) and on the morning of the seventh day. Withdrawal was then elicited by local injection of the opioid antagonist methylnaloxonium into the LC, PAG, or amygdala. Withdrawal signs were precipitated in a dose-dependent manner following injection into the LC or PAG, but not the amygdala. The withdrawal behaviors elicited from the LC and PAG included both the same and different behaviors. The results support the hypothesis that the neural circuitry mediating opiate withdrawal behaviors is similar in infant and adult animals, but the behaviors expressed are age-specific.

Topics: Age Factors; Amygdala; Animals; Animals, Newborn; Behavior, Animal; Disease Models, Animal; Dose-Response Relationship, Drug; Female; Locus Coeruleus; Male; Morphine; Naloxone; Naltrexone; Narcotic Antagonists; Neural Pathways; Opioid-Related Disorders; Periaqueductal Gray; Quaternary Ammonium Compounds; Rats; Rats, Long-Evans; Substance Withdrawal Syndrome